Project Summary/Abstract Concurrent chemoradiation therapy (CCRT) is a common treatment modality for head and neck cancers. Chemotherapy acts as a radiation therapy sensitizer, enhancing the effects of radiation on the target head and neck tissues and increasing oncologic efficacy. Due to its comparable cure rates to surgical management and benefit of organ preservation, CCRT has been increasingly utilized for various head and neck cancers with excellent curative results. However, this treatment modality is associated with significant side effects within the head and neck such as xerostomia, trismus, osteoradionecrosis, mucositis, dysgeusia, dysphonia, and dysphagia, primarily due to the radiation effects on normal tissue surrounding the tumor. Dysphagia can be particularly devastating, as it significantly alters quality of life and is associated with increased risk of aspiration pneumonia. Although muscle weakness and fibrosis are putative causes for swallow dysfunction following CCRT, very little research has been performed to study the underlying mechanisms of this dysfunction. Radiation therapy resulting in fibrosis and, therefore, decreased function has been documented in human tissue within the heart, lungs, and breast. However, within the tongue, and, specifically skeletal muscle, the effects of radiation remain controversial. Multiple translational studies have demonstrated that decreased tongue strength occurs after radiation, but the cause of this weakness is unknown. Four predominant hypotheses have been proposed to explain the skeletal muscle changes following radiation exposure: 1) alteration in cellular metabolism and protein degradation, 2) altered satellite cell concentration and function, 3) fibrosis and muscle atrophy and 4) failure of tissue regeneration. To date, few of these hypotheses have been systematically pursued to the degree required to determine etiology. Most of the literature has focused on fibrosis, but studies have yet to definitively demonstrate consistent fibrosis in muscle as a result of CCRT. In fact, the only human study to specifically examine tissue from the head and neck following CCRT failed to demonstrate significant fibrosis. Most studies have focused solely on animal models of radiation therapy and deliver very high doses of non-targeted radiation, limiting the translational value of the data. In order to better understand the etiology of muscle injury following CCRT, proper dosing must be applied and the tissues fully analyzed to test various hypotheses for muscle dysfunction. The current proposal seeks to elucidate the pathophysiology of muscle dysfunction following delivery of concurrent chemoradiation to the head and neck for definitive treatment of malignancy. The study is translational in that it tests the various hypotheses in both animal and human models.